中脑多巴胺神经元在TBI后执行功能障碍中的作用及机制研究

The mesocortical pathway projecting from dopaminergic neurons in the ventral tegmental area (VTA) and substantia nigra (SN) to the prefrontal cortex plays a critical role in executive function. Accumulating studies demonstrate close associations between impaired executive function and dysfunction of mesocortical pathway in Parkinson’s disease and schizophrenia.Our previous data showed that traumatic brain injury (TBI) can induce dopaminergic neurons injury. Simultaneously, TBI can cause impaired executive function. Unfortunately, no direct evidence verify the connection of injured midbrain dopaminergic neurons with impaired executive function following TBI. In the present study, TBI patients without frontal injuries are recruited. Neuromelanin sensitive MRI and SWI are employed to evaluate TBI-associated damages in the VTA and SN, fMRI is used to identify the working memory induced activity in the VTA, SN and prefrontal cortex, aiming to explain the correlation of injured midbrain with impaired executive function following TBI. In order to confirm the potential effects of midbrain dopaminergic neurons on impaired executive function induced by TBI, we examine working memory in TBI rats without frontal injuries after enhancing or attenuating the function of midbrain dopaminergic neurons. Furthermore, we investigate the effects of dopamine signals in the prefrontal cortex on impaired executive function and regulatory effects of dopamine on GABA neurons in the prefrontal cortex in rats following TBI. Our findings will support our midbrain dopaminergic neuron hypothesis: TBI can cause midbrain dopaminergic neuron damage, and njured.dopaminergic neurons give rise to disturbed dopamine signals in the prefrontal cortex through mesocortical pathway, which in turn lead to impaired executive function.

中脑VTA和SN的DA神经元发出纤维投射到前额叶等区域，形成中脑-皮层通路，该通路在执行功能中发挥重要作用，与PD和精神分裂症患者执行功能障碍密切相关。TBI引起执行功能障碍，我们发现，TBI引起中脑DA神经元损伤。目前，缺乏直接证据将二者联系起来。选取无额叶损伤的TBI患者，采用神经黑色素敏感MRI和SWI，测定VTA和SN神经黑色素和铁含量，采用功能性MRI，研究VTA和SN、前额叶各脑区参与工作记忆的功能状态，明确VTA和SN结构损伤和功能状态与TBI后执行功能的相关性。利用无额叶损伤的TBI大鼠，观察增强或降低中脑DA神经元功能对TBI大鼠执行功能的影响，研究前额叶DA信号在TBI后执行功能障碍中的作用，DA对前额叶GABA神经元的调控，验证“中脑多巴胺神经元”假说：TBI导致中脑DA神经元损伤，中脑DA神经元通过中脑-皮层通路释放到前额叶皮层的DA信号发生紊乱，导致执行功能障碍。

认知障碍和情绪障碍是创伤性颅脑损伤患者常见的后遗症，严重影响患者的预后。我们建立“创伤性颅脑损伤后认知情绪障碍”的研究队列，采用韦氏记忆量表多维度评价受试者的执行功能，采用简易精神状态量表（MMSE）、住院病人焦虑抑郁量表—焦虑（HADS-A）、住院病人焦虑抑郁量表—抑郁（HADS-D）评价被试者的精神状态，采用多模态神经影像技术评价被试者脑结构和功能，制备颅脑损伤小鼠模型，观察DA-JC4对创伤性颅脑损伤小鼠的记忆功能及抑郁样行为的影响。结果发现：1、创伤性颅脑损伤患者的执行功能明显降低，表现出更多的焦虑和抑郁症状。2、与健康对照者相比，TBI患者左侧和右侧的黑质体积均显著较小，而且TBI患者左侧黑质体积较右侧明显减少，提示TBI可导致患者左侧黑质损伤更加明显，DTI结果表明创伤性颅脑损伤可导致中脑-皮层传导束损伤，组间T检验结果表明，创伤性颅脑损伤患者左侧SN的功能连接显著降低，其中左侧SN-左侧角回、左侧SN-左侧中扣带回、左侧SN-左侧额中回的功能连接和创伤性颅脑损伤后焦虑症状的严重程度密切相关，与执行功能相关性不显著。相关分析结果显示，创伤性颅脑损伤患者两侧SN的功能连接和执行功能呈正相关，左侧SN的功能连接和焦虑症状呈正相关。3、创伤性颅脑损伤可导致中脑VTA和SN投射区的结构和功能改变。创伤性颅脑损伤患者右侧楔前叶功能连接的局部一致性（ReHo）显著增加，其和执行功能呈负相关，而与焦虑抑郁症状不相关。右楔前叶ReHo增高与右楔前叶与海马旁回功能连接降低有关。创伤性颅脑损伤患者两侧间额中回及颞中叶的镜像同伦功能连接（VMHC）显著降低，颞中回的VMHC和执行功能相关，额中回的VMHC和焦虑和抑郁症状显著相关。4、对中脑多巴胺神经元具有保护作用的DA-JC4可以改善颅脑损伤小鼠的记忆功能，减轻抑郁样行为。我们的结果提示，多巴胺神经元的中脑-皮层通路与创伤性颅脑损伤后执行功能障碍和情绪障碍的发生密切相关。